The chief goal is to understand how the hormone vasopressin regulates water excretion by the kidney. Vasopressins action is mediated through regulation of the molecular water channel aquaporin-2. Based on our studies a decade ago, it is now clear that vasopressin regulates aquaporin-2 in a time frame of seconds to minutes by altering the distribution of the water channel aquaporin-2 between the plasma membrane and the cytoplasm via vesicular trafficking. Trafficking of aquaporin-2 to the plasma membrane renders the cells permeable to water. We are presently using a systems approach to address the mechanisms involved. For this approach, we are integrating protein mass spectrometry, DNA microarrays, mathematical modeling and physiological methods. The following is a summary of work over the past year appearing in the 32 references published in 2006 and so far in 2007. [unreadable] The first 8 references in the reference list below show publications that have used protein mass spectrometry (1-8) to investigate protein networks involved in regulation of renal water and solute transport. The next four references (9-12) are clinically-oriented papers which describe bioengineering work to exploit our recent discovery that normal kidneys excrete exosomes in the urine. Exosomes are are small membrane particles secreted by every cell type facing the urinary space in the kidney. The goal of these studies is to develop the methods infrastructure to allow clinical investigators to isolate urinary exosomes for disease biomarker studies (9-12). The next 11 references describe work focusing on the use of animal models of disease processes to discover the pathophysiological basis of salt and water imbalance disorders (13-23). The disorders under investigation are nephrogenic diabetes insipidus, urinary tract obscruction, hepatic cirrhosis, congestive heart failure, gentamicin-induced nephrotoxicity, and hypertension. These studies, using methods developed in our laboratory in the 1990s, are done in a collaboration with former post-doctoral fellow Soren Nielsen. The next two papers (24,25) report similar studies on blood pressure regulation done with two other collaborators and former laboratory members, Susan Wall of Emory University and Randall Packer of George Washington University. The final seven papers address how the kidney concentrates solutes in the urine, making heavy use of transgenic and knockout mice(26-32).